BACKGROUND Spinal cord injury (SCI) results in glial scar formation and irreversible neuronal loss, which finally leads to functional impairments and long-term disability. Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs). However, it remains unclear whether treatment with Zfp521 also affects endogenous astrocytes, thus promoting further functional recovery following SCI. METHODS Rat astrocytes were transdifferentiated into neural stem cells in vitro by ZFP521 or Sox2. Then, ZFP521 was applied to the spinal cord injury site of a rat. Transduction, real-time PCR, immunohistofluorescence, and function assessments were performed at 6 weeks post-transduction to evaluate improvement and in vivo lineage reprogramming of astrocytes. RESULTS Here, we show that Zfp521 is more efficient in reprogramming cultured astrocytes compared with Sox2. In the injured spinal cord of an adult rat, resident astrocytes can be reprogrammed into neurons through a progenitor stage by Zfp521. Importantly, this treatment improves the functional abilities of the rats as evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and further by calculation of its subscores. There was enhanced locomotor activity in the hind limbs, step length, toe spread, foot length, and paw area. In addition, motor evoked potential recordings demonstrated the functional integrity of the spinal cord. CONCLUSIONS These results have indicated that the generation of iNSCs or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair.

中文翻译：

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通过单个锌指转录因子在受损脊髓中通过神经干细胞将大鼠星形胶质细胞体内转化为神经元细胞。

背景技术脊髓损伤（SCI）导致神经胶质瘢痕形成和不可逆的神经元丢失，最终导致功能障碍和长期残疾。我们以前的研究表明Zfp521的异位表达将成纤维细胞和星形胶质细胞重编程为诱导的神经干细胞（iNSC）。然而，尚不清楚用Zfp521的治疗是否还会影响内源性星形胶质细胞，从而促进SCI后的进一步功能恢复。方法通过ZFP521或Sox2将大鼠星形胶质细胞体外转分化为神经干细胞。然后，将ZFP521施用于大鼠的脊髓损伤部位。转导后6周进行转导，实时PCR，免疫组织荧光和功能评估，以评估星形胶质细胞的改善和体内谱系重编程。结果在这里，我们显示，与Sox2相比，Zfp521在重编程培养的星形胶质细胞方面更有效。在成年大鼠受伤的脊髓中，Zfp521可以通过祖细胞阶段将驻留的星形胶质细胞重编程为神经元。重要的是，根据Basso，Beattie和Bresnahan（BBB）运动评分量表以及通过计算其子评分来评估，这种治疗可改善大鼠的功能能力。后肢，步长，脚趾展开，脚长和脚掌区域的运动能力增强。另外，运动诱发电位记录证明了脊髓的功能完整性。结论这些结果表明，通过原位重编程从内源性星形胶质细胞生成iNSC或神经元可能是SCI修复的潜在策略。